PROJECT SUMMARY The proposed research focuses on the development of novel therapeutic agents for the treatment of malaria caused by P. falciparum. Preliminary studies have discovered novel natural product and derivative molecules with potent in vitro activity against both sensitive and multidrug resistant malaria strains including a newly emerging artemisinin resistant parasite line. New compounds are low in toxicity and possess good therapeutic indice. This SBIR Phase I project aims to obtain proof of concept in vivo PK, efficacy, and toxicity data. Studies include: (I) Scale up isolation and purification of natural product and synthesis of derivative compounds; (II) Pharmacokinetic (PK) studies; (III) In vivo efficacy studies in SCID mouse P. falciparum model; (IV) In vivo evaluation for acute and sub-acute toxicity, developmental toxicity, and neurotoxicity. The novelty of the project is the discovery of new molecular entities. The project involves standard approaches to drug development, but the multidisciplinary team that has been assembled will accelerate the generation of preclinical candidates.